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Explores politically charged topics through a series of essays by thinkers at the leading edge of educational innovation. It shows how failing schools destroy neighborhoods- not the reverse- and how research reveals that dedicated, attentive teachers are what help at-risk kids succeed.

In the diseased heart, cardiomyocytes undergo necrotic cell death. A healing response results in myofibroblast production of collagen and other matrix molecules, which initially serve to preserve the structural integrity of the myocardium. However, myofibroblast dispersion fails to occur in many cardiac diseases, and perpetual matrix formation leads to adverse remodelling of the heart. In this Review, Weber et al . discuss relevant mechanisms of cardiac fibrosis and consequent remodelling, and highlight potential strategies for cardioprotection. The syncytium of cardiomyocytes in the heart is tethered within a matrix composed principally of type I fibrillar collagen. The matrix has diverse mechanical functions that ensure the optimal contractile efficiency of this muscular pump. In the diseased heart, cardiomyocytes are lost to necrotic cell death, and phenotypically transformed fibroblast-like cells—termed 'myofibroblasts'—are activated to initiate a 'reparative' fibrosis. The structural integrity of the myocardium is preserved by this scar tissue, although at the expense of its remodelled architecture, which has increased tissue stiffness and propensity to arrhythmias. A persisting population of activated myofibroblasts turns this fibrous tissue into a living 'secretome' that generates angiotensin II and its type 1 receptor, and fibrogenic growth factors (such as transforming growth factor-β), all of which collectively act as a signal–transducer–effector signalling pathway to type I collagen synthesis and, therefore, fibrosis. Persistent myofibroblasts, and the resultant fibrous tissue they produce, cause progressive adverse myocardial remodelling, a pathological hallmark of the failing heart irrespective of its etiologic origin. Herein, we review relevant cellular, subcellular, and molecular mechanisms integral to cardiac fibrosis and consequent remodelling of atria and ventricles with a heterogeneity in cardiomyocyte size. Signalling pathways that antagonize collagen fibrillogenesis provide novel strategies for cardioprotection. Key Points The muscular parenchyma of the heart, a syncytium of cardiomyocytes, is tethered within a structural protein network primarily composed of type I fibrillar collagen The matrix promotes transmission and coordination of forces generated within myofibres, prevents myofibre slippage while sustaining chamber geometry without deformation, and protects against myocardial rupture When cardiomyocytes are lost to necrosis, fibroblast-like cells restore structural integrity of the myocardium and form a 'secretome' that exerts autocrine and paracrine actions to regulate collagen turnover An adverse cell–cell interaction ensues between persistent myofibroblasts and cardiomyocytes, which negatively influences electrical behaviour of the myocardium, predisposing it to arrhythmias Tendrils of myofibroblast-generated collagen can ensnare cardiomyocytes, resulting in reduced workload and, therefore, disuse atrophy of these cells Key targets for downregulating matrix responses and, therefore, for cardioprotection lie in the myofibroblast secretome

The potent mineralocorticoid aldosterone has a multifaceted role in the pathogenesis of congestive heart failure. In addition to its contribution to salt and water retention, it also promotes organ fibrosis. Although angiotensin-converting–enzyme inhibitors have important therapeutic benefit in heart failure, they do not eliminate the effects of aldosterone. Thus, recent studies have underscored the value of aldosterone-receptor antagonists, such as spironolactone, in the treatment of chronic heart failure. This review article gives an in-depth update on the mechanisms of action of aldosterone and their implications for therapy. Aldosterone was isolated from blood and urine, its adrenal origin elucidated, and its steroid structure identified nearly 50 years ago. Actions involving the reabsorption of sodium and the release of potassium by epithelial cells in the kidneys, intestine, and sweat and salivary glands led to its designation as a mineralocorticoid. The physiologic importance of aldosterone in preventing the loss of salt and water during periods of dietary sodium deprivation is now clear. Its contribution to the retention of sodium in patients with congestive heart failure, cirrhosis, and the nephrotic syndrome has also been established. 1 – 3 The perception of its pathophysiologic . . .

\"Lincoln, in theaters November 9, portrays America's 16th president when he faced two colossal challenges: winning the Civil War, and passing the Thirteenth Amendment, outlawing slavery and making permanent the promise of the Emancipation Proclamation. The politics of wartime, which required unity at all costs, conflicted with divisiveness of slavery. The president had to be at once true to his ideals and employ old-fashioned political cunning to outwit his rivals. This companion book, featuring a foreword by screenwriter Tony Kushner, invites historians and Lincoln experts to imagine Lincoln in eras other than his own, facing challenges of those times. How would Lincoln have handled the Second World War, or the politics of Civil Rights era, or the modern Republican Party? Using the character of Lincoln presented in the film - a man of high principle and low cunning - the book shows how Lincoln, a president for the ages, might indeed have taken America forward during other historic moments of drama and opportunity. \"-- Provided by publisher.

Mitochondria are complex organelles that play critical roles in diverse aspects of cellular function. Heart disease and a number of other pathologies are associated with perturbations in the molecular machinery of the mitochondria. Therefore, comprehensive, unbiased examination of the mitochondrial proteome represents a powerful approach toward system-level insights into disease mechanisms. A crucial aspect in proteomics studies is design of bioanalytical strategies that maximize coverage of the complex repertoire of mitochondrial proteins. In this study, we evaluated the performance of gel-based and gel-free multidimensional platforms for profiling of the proteome in subsarcolemmal mitochondria harvested from rat heart. We compared three different multidimensional proteome fractionation platforms: polymeric reversed-phase liquid chromatography at high pH (PLRP), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and isoelectric focusing (IEF) separations combined with liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS), and bioinformatics for protein identification. Across all three platforms, a total of 1043 proteins were identified. Among the three bioanalytical strategies, SDS-PAGE followed by LC-MS/MS provided the best coverage of the mitochondrial proteome. With this platform, 890 proteins with diverse physicochemical characteristics were identified; the mitochondrial protein panel encompassed proteins with various functional roles including bioenergetics, protein import, and mitochondrial fusion. Taken together, results of this study provide a large-scale view of the proteome in subsarcolemmal mitochondria from the rat heart, and aid in the selection of optimal bioanalytical platforms for differential protein expression profiling of mitochondria in health and disease.

Heart failure and hypertension have each been linked to an induction of oxidative stress transduced by neurohormones, such as angiotensin II and catecholamines. Herein, we hypothesized that aldosterone (ALDO) likewise induces oxidative stress and accounts for a proinflammatory/fibrogenic phenotype that appears at vascular and nonvascular sites of injury found in both right and left ventricles in response to ALDO/salt treatment and that would be sustained with chronic treatment. Uninephrectomized rats received ALDO (0.75 micro g/hour) together with 1% dietary NaCl, for 3, 4, or 5 weeks. Other groups received this regimen in combination with an ALDO receptor antagonist, spironolactone (200 mg/kg p.o. daily), or an antioxidant, either pyrrolidine dithiocarbamate (PDTC) (200 mg/kg s.c. daily) or N-acetylcysteine (NAC) (200 mg/kg i.p. daily). Unoperated and untreated age- and gender-matched rats served as controls. We monitored spatial and temporal responses in molecular and cellular events using serial, coronal sections of right and left ventricles. Our studies included: assessment of systolic blood pressure; immunohistochemical detection of NADPH oxidase expression and activity; analysis of redox-sensitive nuclear factor-kappaB activation; in situ localization of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha mRNA expression; monitoring cell growth and infiltration of macrophages and T cells; and analysis of the appearance and quantity of fibrous tissue accumulation. At week 3 of ALDO/salt treatment and comparable to controls, there was no evidence of oxidative stress or pathological findings in the heart. However, at weeks 4 and 5 of treatment, increased gp91(phox) and 3-nitrotyrosine expression and persistent activation of RelA were found in endothelial cells and inflammatory cells that appeared in the perivascular space of intramural coronary arteries and at sites of lost cardiomyocytes in both ventricles. Coincident in time and space with these events was increased mRNA expression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha. Macrophages, lymphocytes, and proliferating endothelial and vascular smooth muscle cells and fibroblast-like cells were seen at each of these sites, together with an accumulation of fibrillar collagen, or fibrosis, as evidenced by a significant increase in ventricular collagen volume fraction. Co-treatment with spironolactone, PDTC, or NAC attenuated these molecular and cellular responses as well as the appearance of fibrosis at vascular and nonvascular sites of injury. Furthermore, elevated systolic blood pressure in ALDO-treated rats was partially suppressed by spironolactone or either antioxidant. Thus, chronic ALDO/salt treatment is accompanied by a time-dependent sustained activation of NADPH oxidase with 3-nitrotyrosine generation and nuclear factor-kappaB activation expressed by endothelial cells and inflammatory cells. This leads to a proinflammatory/fibrogenic phenotype involving vascular and nonvascular sites of injury found, respectively, in both normotensive and hypertensive right and left ventricles. Spionolactone, PDTC, and NAC each attenuated these responses suggesting ALDO/salt induction of oxidative/nitrosative stress is responsible for the appearance of this proinflammatory phenotype.

Proper spindle positioning and orientation are essential for asymmetric cell division and require microtubule–actin filament (F-actin) interactions in many systems 1 , 2 . Such interactions are particularly important in meiosis 3 , where they mediate nuclear anchoring 4 , 5 , 6 , as well as meiotic spindle assembly and rotation 7 , 8 , two processes required for asymmetric cell division. Myosin-10 proteins are phosphoinositide-binding 9 , actin-based motors that contain carboxy-terminal MyTH4 and FERM domains of unknown function 10 . Here we show that Xenopus laevis myosin-10 (Myo10) associates with microtubules in vitro and in vivo , and is concentrated at the point where the meiotic spindle contacts the F-actin-rich cortex. Microtubule association is mediated by the MyTH4-FERM domains, which bind directly to purified microtubules. Disruption of Myo10 function disrupts nuclear anchoring, spindle assembly and spindle–F-actin association. Thus, this myosin has a novel and critically important role during meiosis in integrating the F-actin and microtubule cytoskeletons.